The major objective of this on going program is resolution of the hypothesis developed in this laboratory that significant components of alcoholism arise from aberrant neuroamine metabolism resulting in formation of benzyltetrahydroisoquinoline alkaloids which can be further metabolized to even more complex pharmacologically active alkaloids. We propose to utilize newly developed technology to assess endogenous formation of tetrahydroisoquinoline alkaloids in experimental animals chronically exposed to ethanol and in human alcoholics. The new analytical approach we have developed incorporated markedly improved isolation procedures and sensitive HPLC ad GC/MS technology for detection and identification of tetrahydropapaveroline and its metabolites which should allow definitive evaluation of their ethanol-mediated formation. Additionally, biochemical, pharmacologic and behavioral effects of chronic ethanol administration and exogenously administered alkaloids on the functional integrity of selected dopaminergic pathways will be assess in experimental animals and human alcoholics. The long range goal is to obtain information that will be instrumental in elucidating underlying neuropharmacologic actions of ethanol and neuroamine-derived alkaloids in alcohol related disorders.